2-Oxo-piperidinyl- and 2-oxo-azepanyl alkanoic acid derivatives for the treatment of epilepsy and other neurological disorders

ABSTRACT

This invention relates to new 2-oxo-piperidinyl- and 2-oxo-azepanyl alkanoic acid derivatives of formula (1) having anticonvulsant activity which are useful as therapeutic agents for the treatment or prevention of epilepsy and other neurological disorders. The invention also concerns processes for preparing these derivatives and novel intermediates used in the preparation of these derivatives.

This is a divisional of Ser. No. 10/476,791, filed Nov. 6, 2003, whichis a 371 of PCT/EP02/05503, filed May 17, 2002.

FIELD OF THE INVENTION

This invention relates to new 2-oxo-piperidinyl- and 2-oxo-azepanylalkanoic acid derivatives leaving anticonvulsant activity which areuseful as therapeutic agents for the treatment and/or prevention ofepilepsy and other neurological disorders. The invention also concernsprocesses for preparing these derivatives and novel intermediates usedin the preparation of these derivatives.

BACKGROUND OF THE INVENTION

Epilepsy is a relatively common neurological condition affecting 0.4-1%of the world's population (45-100 million people). For the generalpopulation there are approximately 20-70 new cases per 100,000 diagnosedeach year With a 3-5% lifetime probability of developing the disease.The older established antiepileptic drugs (AEDs) phenytoin,carbamazepine, clonazepam, ethosuximide, valproic acid and barbituratesare widely prescribed but suffer from a range of side effects.Furthermore, there is a significant group of patients (20-30%) that areresistant to the currently available therapeutic agents. Since 1989several new drugs have been launched, including felbamate, gabapentin,lamotrigine, oxcarbazepine, tiagabine, topimarate, vigabatrin,zonisamide and levetiracetam. While many of the new AEDs show improvedefficacies and side-effect profiles, patients with intractable epilepsyremain untreated. There is clearly a need for improved medications(Cosford N. D. P. et al., Annual Reports in Medicinal Chemistry (1998).33, 61-70).

U.S. Pat. No. 6,066,666 reports lactam and thiolactam derivatives havinguseful anticonvulsant and anxiolytic activity, and thus being effectivein the treatment of epilepsy.

U.S. Pat. No. 5,334,720 relates to diptenyl-1-(aminoalkyl)-2-piperidoneand -2-pyrrolidinone derivatives, which possess anticonvulsantproperties and are useful anti-epileptic agents.

European Patent No. 0 162 036 B1 discloses levetiracetam or(S)-(−)-α-ethyl-2-oxo-1-pyrrolidineacetamide as well as its use as aprotective agent for the treatment and the prevention of hypoxic andischemic type aggressions of the central nervous system. This compoundis also effective in the treatment of epilepsy, a therapeutic indicationfor which it has been demonstrated that its dextrorotatory enantiomer(R)-(+)-α-ethyl-2-oxo-1-pyrrolidineacetamide completely lacks activity(Gower A. J. et al., Eur. J. Pharmacol. (1992), 222, 193-203). In theEuropean Patent No. 0 645 139 B1, levetiracetam has been disclosed forits anxiolytic activity. International Patent Application No.PCT/EP00/11808 discloses the use of levetiracetam for the curativeand/or prophylactic treatment of bipolar disorders, migraine, chronic orneuropathic pain as well as combinations of levetiracetam with at leastone compound inducing neural inhibition mediated by GABA_(A) receptors.

Continuing Its research work in the field of the treatment of epilepsy,the applicant discloses now new 2-oxo-piperidinyl- and 2-oxo-azepanylalkanoic acid derivatives. These new 2-oxo-piperidinyl- and2-oxo-azepanyl alkanoic acid derivatives are useful for the preventionor the treatment of epilepsy, epileptogenesis, seizure disorders andconvulsions.

These compounds may also be used for the treatment of other neurologicaldisorders including bipolar disorders, mania, depression, anxiety,migraine, trigeminal and other neuralgia, chronic pain, neuropathicpain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse,stroke, myoclonus, essential tremor and other movement disorders,neonatal cerebral haemorrhage, amyotrophic lateral sclerosis,spasticity, Parkinson's disease and other degenerative diseases.

In addition the compounds according to the invention may be used in thetreatment of bronchial asthma, asthmatic status and allergic bronchitis,asthmatic syndrome, bronchial hyperreactivity and bronchospasticsyndromes as well as allergic and vasomotor rhinitis andrhinoconjunctivitis.

DESCRIPTION OF THE INVENTION

This invention provides novel compounds of the formula I

wherein

n represents 0 or 1 whereby R¹ is not existent when n=0 and R¹ isexistent when n=1;

A¹ represents an oxygen or a sulfur atom;

X is —CONR⁷R⁸, —COOR⁹, —CO—R¹⁰ or CN;

R¹ when existent, R², R³, R⁴ and R⁵ are the same or different and eachis independently hydrogen, halogen, hydroxy, thiol, amino, nitro,nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide,alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an oxyderivative, thio derivative, amino derivative, acyl derivative, sulfonylderivative or sulfinyl derivative,

provided that at least one of the substituents R chosen from R¹ whenexistent, R², R³, R⁴ or R⁵ is not hydrogen;

R⁶ is hydrogen, alkyl, aryl or —CH₂—R^(6a) wherein R^(6a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

R⁷, R⁸ and R⁹ are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; and

R¹⁰ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or athio derivative;

their pharmaceutically acceptable salts, geometrical Isomers (includingcis and trans, Z and E isomers), enantiomers, diastereoisomers andmixtures thereof (including all possible mixtures of stereoisomers).

In the above formula, at least one substituent R¹ to R⁵ is differentfrom hydrogen. Some non-substituted compounds are disclosed in U.S. Pat.Nos. 5,468,733 and 5,516,759. U.S. Pat. No. 5,468,733 discloses non-ringsubstituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinyl derivatives asinhibitors of the oncogene Ras protein. In particular, these compoundsblock the ability of Ras to transform normal cells to cancer cells, andtherefore can be included in several chemotherapeutic compositions fortreating cancer.

US Patent No. 5,516,759 discloses non-ring substituted2-oxo-l-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl derivativespresent at the N-terminus of dodecapeptides possessing LHRH (luteinizinghormone-releasing hormone) antagonistic activity. Such LHRH antagonistsare useful in the treatment of a variety of conditions in whichsuppression of sex steroids plays a key role including contraception,delay of puberty, treatment of benign prostatic hyperplasia a.o.

In the definitions set forth below, unless otherwise stated, R¹¹ and R¹²are the same or different and each is independently amido, alkyl,alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or anoxy derivative, thio derivative, acyl derivative, amino derivative,sulfonyl derivative, or sulfinyl derivative, each optionally substitutedwith any suitable group, including, but not limited to, one or moremoieties selected from lower alkyl or other groups as described below assubstituents for alkyl.

The term “oxy derivative”, as used herein, is defined as including—O—R¹¹ groups wherein R¹¹ is as defined above except for “oxyderivative”. Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy,acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy,arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxysuch as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy,2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.

The term “thio derivative”, as used herein, is defined as including—S—R¹¹ groups wherein R¹¹ is as defined above except for “thioderivative”. Non-limiting examples are alkylthio, alkenylthio,alkynylthio and arylthio.

The term “amino derivative”, as used herein, is defined as including—NHR¹¹ or —NR¹¹R¹² groups wherein R¹¹ and R¹² are as defined above.Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- andarylamino or mixed amino.

The term “acyl derivative”, as used herein, represents a radical derivedfrom carboxylic acid and thus is defined as including groups of theformula R¹¹—CO—, wherein R¹¹ is as defined above and may also behydrogen. Preferred are acyl derivatives of formula —COR¹¹ wherein R¹¹is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkenyl,heterocyle and aryl. Non-limiting examples are formyl, acetyl,propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl,cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl,furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl,oxamoyl.

The term “sulfonyl derivative”, as used herein, is defined as includinga group of the formula —SO—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfonyl derivative”. Non-limiting examples are alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term “sulfinyl derivative”, as used herein, is defined as includinga group of the formula —SO—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfinyl derivative”. Non-limiting examples are alkylsulfinyl,alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and generally containing 1-20 carbonatoms, most often 1 to 12 carbon atoms, preferably 1-7 carbon atoms fornon-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these twopreferred cases, unless otherwise specified, “lower alkyl”), eachoptionally substituted by, preferably 1 to 5, substituents independentlyselected from the group consisting of halogen, hydroxy, thiol, amino,nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinylderivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl,sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester,oxyamido, heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy(preferably C6-10) and aryl(preferably C6-10).

Preferred are alkyl groups containing 1 to 7 carbon atoms, eachoptionally substituted by one or more substituents selected fromhydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio,cyclopropyl, acyl and phenyl. Most preferred are C1-4 alkyl and C3-7cycloalkyl, each optionally substituted by one or more hydroxy, halogen,lower alkyl or/and azido.

Most preferred alkyl groups are hydroxymethyl, propyl, butyl,2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl,2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

The term “lower alkyl”, as used herein, and unless otherwise specified,refers to C₁ to C₇ saturated straight, branched or cyclic hydrocarbon.Non limiting examples are methyl, ethyl, propyl, isopropyl, butyl,tertiobutyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl,hexyl, isohexyl, cyclohexyl, 3-methypentyl, 2,2-dimethylbutyl,optionally substituted with any suitable group, including but notlimited to one or more moieties selected from groups as described abovefor the alkyl groups. Preferably, lower alkyl is methyl.

The term “alkenyl”, as used herein, is defined as including bothbranched and unbranched, unsaturated hydrocarbon radicals having atleast one double bond, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro,cyano, aryl and heterocycle.

Prefered alkenyl groups are C2-C12 alkenyls, especially C2-6alkenyls,such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl,1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl,4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl,2-hexenyl and the like, optionally being substituted by one or moresubstituents selected from halogen, cyano, thiocyanato, azido,alkylthio, cycloalkyl, phenyl and acyl. Most prefered is vinyl,optionally substituted by one or more halogen or/and lower alkyl, andespecially 2,2-difluorovinyl, 2,2-dibromovinyl and 2,2-dichlorovinyl.

The term “alkynyl” as used herein, is defined as including a monovalentbranched or unbranched hydrocarbon radical containing at least onecarbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl),and the like, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido,alkylthio, alkyl and acyl.

Preferred alkynyl groups are C2-12 alkynyl, especially C2-6 alkynyl,optionally being substituted by one or more substituents selected fromhalogen, cyano, thiocyanato, azido, alkylthio, acyl, aryl such as phenyland alkyl, preferably cycloalkyl.

Most preferred are ethynyl, propynyl and butynyl, optionally substitutedby lower alkyl or/and halogen, and especially 1-propynyl,cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl representstraight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-,preferably C2-4-alkenylene or -alkynylene moieties respectively.

Groups where branched derivatives are conventionally qualified byprefixes such as “n”, “sec”, “iso” and the like (e.g. “n-propyl”,“sec-butyl”) are in the n-form unless otherwise stated.

The term “aryl”, as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of at least onering, most often 1 to 3 rings and generally containing 6-30 carbon atomsby removal of one hydrogen, such as phenyl and naphthyl, each optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl,sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonicacid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C1-6-alkylthio,oxyester, oxyamido, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl,C1-6-haloalkyl. Aryl radicals are preferably monocyclic or bicycliccontaining 6-10 carbon atoms. Preferred aryl groups are phenyl andnaphthyl each optionally substituted by one or more substituentsindependently selected from halogen, nitro, amino, azido, C1-6-alkoxy,C1-6-alkyl, C1-6-haloalkyl, sulfonyl and phenyl.

Preferred aryl is phenyl, optionally substituted by one or more halogen,lower alkyl, azido or nitro, such as 3-chlorophenyl and 3-azidophenyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The term “cyano”, as used herein, represents a group of the formula —CN.

The term “nitro”, as used herein, represents a group of the formula—NO₂.

The term “nitrooxy”, as used herein, represents a group of the formula—ONO₂.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “azido”, as used herein, represents a group of the formula —N₃.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “sulfonic acid”, as used herein, represents a group of theformula —SO₃H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO₂NH₂.

The term “ester”, as used herein, is defined as including a group offormula —COO—R¹¹ wherein R¹¹ is as defined above except oxy derivative,thio derivative or amino derivative. Preferred are esters of formula—COOR¹¹ wherein R¹¹ is selected from C1-12 alkyl, C2-12 alkenyl, C2-12alkynyl and aryl. Most preferred are esters where R¹¹ is a lower alkyl,especially methyl.

The term “ether” is defined as including a group selected fromC1-50-straight or branched alkyl, or C2-50-straight or branched alkenylor alkynyl groups or a combination of the same, interrupted by one ormore oxygen atoms.

The term “amido” is defined as including a group of formula —CONH₂ or—CONHR¹¹ or —CONR¹¹R¹² wherein R¹¹ rand R¹² are as defined above.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety asdefined above, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl, and optionallybeing substituted with any suitable group, including but not limited toone or more moieties selected from lower alkyl, or other groups asdescribed above for the alkyl groups. Non-limiting examples ofheterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl,triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl,quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl,indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl,1,2,4-thiadiazolyl, thiomorpholinyl, thieno(2,3-b)furanyl, furopyranyl,benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl,benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl,1-oxidopyridyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenothiazinyl, furazanyl, benzodioxolyl, isochromanyl,indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl,morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl,2-oxo-pyrrolidinyl, sugar moieties (i.e. glucose, pentose, hexose,ribose, fructose, which may also be substituted) optionally substitutedby alkyl or as described above for the alkyl groups. The term“heterocycle” also includes bicyclic, tricyclic and tetracyclic, spirogroups in which any of the above heterocyclic rings is fused to one ortwo rings independently selected from an aryl ring, a cyclohexane ring,a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or anothermonocyclic heterocyclic ring or where a monocyclic heterocyclic group isbridged by an alkylene group, such as quinuclidinyl,7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2. 1)heptanyl,8-azabicyclo(3.2.1)octanyl.

The heterocycle is preferably selected from triazolyl, tetrazolyl,pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl,furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyland piperazinyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino,acyl and phenyl. More preferably the heterocycle is selected fromtetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl andthienyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, halogen substituted alkyl, acyl, alkoxy,nitro, amino and phenyl, and especially from 2-and 3-thienyl, optionallysubstituted by one or more halogen, acyl such as formyl, cyano and/orlower alkyl, such as methyl.

In the above definitions it is to be understood that when a substituentsuch as R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰ is attached to the rest ofthe molecule via a heteroatom or a carbonyl, a straight- or branchedchain, C1-12-, preferably C1-4-alkylene or C2-12, preferablyC2-4-alkenylene or -alkynylene bridge may optionally be interposedbetween the heteroatom or the carbonyl and the point of attachment tothe rest of the molecule.

The “pharmaceutically acceptable salts” according to the inventioninclude therapeutically active, non-toxic base and acid salt forms whichthe compounds of formula (I) are able to form.

The acid addition salt form of a compound of formula (I) that occurs inits free form as a base can be obtained by treating said free base formwith an appropriate acid such as an inorganic acid, for example, ahydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric,phosphoric and the like; or an organic acid, such as, for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic,maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt form,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.(1976), 45, 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

Furthermore, certain compounds of formula I which contain alkenyl groupsmay exist as Z (zusammen) or E (entgegen) isomers. In each instance, theinvention includes both mixture and separate individual isomers.

Multiple substituents on the piperidinyl or the azepanyl ring can alsostand in either cis or trans relationship to each other with respect tothe plane of the piperidinyl or the azepanyl ring.

Some of the compounds of formula I may also exist in tautomeric forms.Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof unless the particular isomeric formis referred to specifically.

The invention also includes within its scope prodrug forms of thecompounds of formula I and Its various sub-scopes and sub-groups.

The term “prodrug” as used herein includes compound forms which arerapidly transformed in vivo to the parent compound according to theinvention, for example, by hydrolysis in blood. Prodrugs are compoundsbearing groups which are modified by biotransformation prior toexhibiting their pharmacological action. Such groups include moietieswhich are readily oxidised, cyclised or cleaved, which compound afterbiotransformation remains or becomes pharmacologically active. Forexample, metabolically cleavable groups form a class of groups wellknown to practitioners of the art. They include, but are not limited tosuch groups as alkanoyl (i.e. acetyl, propionyl, butyryl, and the like),unsubstituted and substituted carbocyclic aroyl (such as benzoyl,substituted benzoyl and 1- and 2-naphthoyl), alkoxycarbonyl (such asethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethylsilyl),monoesters formed with dicarboxylic acids (such as succinyl), phosphate,sulfate, sulfonate, sulfonyl, sulfinyl and the like. The compoundsbearing the biotransformable groups have the advantage that they mayexhibit improved bioavailability as a result of enhanced solubilityand/or rate of absorption conferred upon the parent compound by virtueof the presence of the biotransformable group. T. Higuchi and V. Stella,“Pro-drugs as Novel Delivery System”, Vol. 14 of the A.C.S. SymposiumSeries; “Bioreversible Carriers in Drug Design”, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press, 1987.

The term “R substituent” refers to R¹, R², R³, R⁴ or R⁵ , independently.

According to a preferred embodiment, the present invention relates to acompound of formula I as defined above wherein n represents 0. Thecompound is a 6-ring structure (2-thioxo- or 2-oxo-piperidinylderivative) wherein R¹ is not existent since n=0, and is depicted by theformula (I-A).

According to a following embodiment, the present invention relates to acompound of formula I according to the invention as defined abovewherein n represents 1. The compound is a 7-ring structure (2-thioxo- or2-oxo-azepanyl derivative) wherein R¹ is existent since n=1 and depictedby the formula (I-B).

According to a more preferred embodiment, the invention relates to saidcompound as defined above wherein n=0, R³ and/or R⁴ are different fromhydrogen and R² and R⁵ represent hydrogen.

According to another more preferred embodiment, the invention relates tosaid compound as defined above wherein n=1, R², R³ and/or R⁴ aredifferent from hydrogen and wherein R¹ and R⁵ represent hydrogen.

According to a yet more preferred embodiment, the invention relates tosaid compound as defined above wherein only one R substituent chosenfrom R³ or R⁴ when n=0 or from R², R³ or R⁴ when n=1, is different fromhydrogen and the remaining R substituent(s) is/are hydrogen. We herebyrefer to a mono-substituted 2-thioxo- or 2-oxo-piperidinyl or 2-thioxo-or 2-oxo-azepanyl derivatives.

According to another preferred embodiment, the present invention relatesto compounds of formula I according to the invention as defined abovewherein A¹ represents an oxygen atom. We hereby refer to2-oxo-piperidinyl or 2-oxo-azepanyl derivatives.

According to another preferred embodiment, the present invention relatesto compounds of formula I according to the invention as defined abovewherein X is CONR⁷R⁸, especially CONH₂. We hereby refer to amidoderivatives of 2-oxo(or thioxo)-piperidinyl or 2-oxo(orthioxo)-azepanyl.

According to another preferred embodiment, the present invention relatesto compounds of formula I according to the invention as defined abovewherein R⁶ represents hydrogen, C1-4 alkyl, or a CH₂—R^(6a) groupwherein R^(6a) represents a heterocycle. Most preferably R⁶ is a C1-4alkyl, especially ethyl. When R⁶ is ethyl we refer to 2-(2-oxo(orthioxo)-1-piperidinyl)butanamide or 2-(2-oxo(orthioxo)-1-azepanyl)butanamide derivatives.

According to another preferred embodiment, the present invention relatesto compounds of formula I according to the invention as defined abovewherein the carbon atom to which R⁶ is attached is of the Sconfiguration. In case where R⁶ is ethyl, A is oxygen and X is CON R⁷R⁸, we refer then to (2S)-2-(2-oxo-1-piperidinyl)butanamide or(2S)-2-(2-oxo-1-azepanyl)butanamide derivatives.

According to a prefered embodiment, the present invention relates to acompound as defined above wherein R² when n=1, R³ and R⁴ are the same ordifferent and each is independently hydrogen, halogen, nitro, nitrooxy,cyano, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl,alkynyl, ester, ether, aryl, heterocycle, acyl derivative, sulfonylderivative or sulfinyl derivative:

R¹ when existent, R² when n=0 and R⁵ are hydrogen;

R⁶ is hydrogen, alkyl, aryl or —CH₂—R^(6a) wherein R^(6a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

provided that, when R⁶ is hydrogen, X is —CONR⁷R⁸ and that the compoundis

neither methyl (2R)-2-[(6R)-6-methyl-2-oxoazepanyl]-3-phenylpropanoate

nor methyl (2S)-2-[(4R)-4-methyl-2-oxoazepanyl]-3-phenylpropanoate.

According to this preferred embodiment, the compound is generally suchthat when R⁶ is benzyl, X is —COOCH₃ and n=1, R² is different frommethyl when R³ and R⁴ are both hydrogen and R⁴ is different from methylwhen R² and R³ are both hydrogen.

According to another preferred embodiment, the present invention relatesto a compound as defined above wherein R² when n=1, R³ and R⁴ are thesame or different and each is independently hydrogen; cyano; carboxy;amido;

-   C1-12 alkyl, each optionally substituted by one or more substituents    selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,    alkyltio, cycloalkyl, acyl, aryl and heterocycle;-   C2-12 alkenyl, each optionally substituted by one or more    substituents selected from halogen, cyano, thiocyanato, azido,    alkylthio, alkyl, aryl and acyl;-   C2-12 alkynyl, each optionally substituted by one or more    substituents selected from halogen, cyano, thiocyanato, azido,    alkylthio, alkyl, aryl and acyl; acyl derivative of formula —CO—R¹¹,    wherein R¹¹ is selected from C1-12 alkyl, C2-12 alkenyl, C2-12    alkynyl, heterocycle and aryl;-   ester of formula —CO—O—R¹¹ wherein R¹¹ is selected from C1-12 alkyl,    C2-12 alkenyl, C2-12 alkynyl and aryl;-   heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl,    pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl,    oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl    and piperazinyl, each optionally substituted by one or more    substituents selected from halogen, alkyl, substituted alkyl,    alkoxy, nitro, amino, acyl and phenyl;-   aryl, each optionally substitued by one or more substituents    selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6    alkylthio, amino, azido, sulfonyl, aryl and nitro.

According to another preferred embodiment, the present invention relatesto a compound as defined above, wherein R² when n=1, R³ and R⁴ are thesame or different and each is independently hydrogen;

-   C1-7 alkyl, each optionally substituted by one or more substituents    selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,    alkyltio, cyclopropyl, acyl and phenyl;-   C2-6 alkenyl, each optionally substituted by one or more    substituents selected from halogen, cyano, thiocyanato, azido,    alkylthio, cycloalkyl, phenyl and acyl:-   C2-6 alkynyl, each optionally substituted by one or more    substituents selected from halogen, cyano, thiocyanato, azido,    alkylthio, cycloalkyl, phenyl and acyl:-   heterocycle selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl,    pyrrolyl, thiazolyl and thienyl, each optionally substituted by one    or more substituents selected from halogen, alkyl, halogen    substituted alkyl, acyl, alkoxy, nitro, amino and phenyl;-   phenyl, each optionally substitued by one or more substituents    selected from C1-6 alkyl, halogen substituted alkyl, halogen,    alkoxy, amino, azido, sulfonyl, phenyl and nitro.

According to another preferred embodiment, the present invention relatesto a compound as defined above wherein at least one of the Rsubstituents chosen from the group R², R³ and R⁴ when n=1 or from thegroup R³ and R⁴ when n=0, represents independently C1-4-alkyl orC3-7-cycloalkyl, optionally substituted by one or more halogen, hydroxy,lower alkyl and/or azido.

According to another preferred embodiment, the present invention relatesto a compound as defined above wherein at least one of the Rsubstituents chosen from the group R², R³ and R⁴ when n=1 or from thegroup R³ and R⁴ when n=0, represents independently vinyl, optionallysubstituted by one or more halogen or/and lower alkyl.

According to another preferred embodiment, the present invention relatesto a compound as defined above wherein at least one of the Rsubstituents chosen from the group R², R³ and R⁴ when n=1 or from thegroup R3 and R⁴ when n=0, represents independently ethynyl, propynyl orbutynyl, optionally substituted by one or more halogen and/or loweralkyl.

According to another preferred embodiment, the present invention relatesto a compound as defined above wherein at least one of the Rsubstituents chosen from the group R², R³ and R⁴ when n=1 or from thegroup R³ and R⁴ when n=0, represents independently phenyl, optionallysubstituted by one or more halogen, lower alkyl, azido and/or nitro.

According to another preferred embodiment, the present invention relatesto a compound as defined above wherein at least one of the Rsubstituents chosen from the group R², R³ and R⁴ when n=1 or from thegroup R³ and R⁴ when n=0, represents independently 2- or 3-thienyl,optionally substituted by one or more halogen, acyl, cyano or/and loweralkyl.

According to a particular preferred embodiment, the present inventionrelates to a compound as defined above wherein at least one of the Rsubstituents chosen from the group R³, R⁴ and R² when n=1 or from thegroup R³ and R⁴ when n=0, is hydroxymethyl, propyl, butyl,3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl,3-azidophenyl, 2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl,2-ethynyl, 5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl,3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl,1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl,2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl,2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to yet another preferred embodiment, the present inventionrelates to a compound as defined above wherein R¹, R², R⁴ and R⁵ arehydrogen.

According to even another preferred embodiment, the present inventionrelates to a compound as defined above wherein R¹, R², R³ and R⁵ arehydrogen.

According to even another preferred embodiment, the present inventionrelates to a compound as defined above wherein n=1 and R¹, R³, R⁴ and R⁵are hydrogen.

In all the above-mentioned scopes when the carbon atom to which R⁶ isattached is asymmetric it is preferably in the “S”-configuration.

Representative compounds of this invention as defined above are selectedfrom the group consisting of2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-propyl-1-piperidinyl)butanamide,2-12-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,2-[2-oxo-5-(2-thienyl)-1-piperidinyl]butanamide,2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide,2-[5-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide,2-[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide,2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-difluoropropyl)-2-oxo 1-piperidinyl]butanamide,2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-4-propyl-1-piperidinyl)butanamide,2-[2-oxo-4-(3,3,3-trifluoroproyl)-1-piperidinyl]butanamide,2-14-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(iodomethyl)-2-oxo-1-piperldinyl]butanamide,2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,2-12-oxo-4-(2-thienyl)-1-piperidinyl]butanamide,2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide,2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,2-[2-oxo-4-( 1-propynyl)-1-piperidinyl]butanamide,2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-14-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-5-propyl-1-azepanyl)butanamide,2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-(5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-5-phenyl-1-azepanyl)butanamide,2-[2-oxo-5-(2-thienyl)-1-azepanyl]butanamide,2-[2-oxo-5-(3-thienyl)-1-azepanyl]butanamide,2-[5-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(5-ethynyl-2-oxo-1-azepanyl)butanamide,2-[5-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2-[2-oxo-5-(1-propynyl)-1-azepanyl]butanamide,2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-6-propyl-1-azepanyl)butanamide,2-[2-oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-16-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-6-phenyl-1-azepanyl)butanamide,2-[2-oxo-6-(2-thienyl)-1-azepanyl]butanamide,2-[2-oxo-6-(3-thienyl)-1-azepanyl]butanamide,2-[6-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(6-ethynyl-2-oxo-1-azepanyl)butanamide,2-[6-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(4-methyl-2-thienyl]-2-oxo-1-azepanyl]butanamide,2-[2-oxo-6-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2-[2-oxo-6-(1-propynyl)-1-azepanyl]butanamide,2-[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-4-propyl-1-azepanyl)butanamide,2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-14-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-4-phenyl-1-azepanyl)butanamide,2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide,2-[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide,2-f4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(4-ethynyl-2-oxo-1-azepanyl)butanamide,2-[4-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[⁴-(5-cyano-²-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2-[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide,2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2-chloro-2,2-difluoroethyl]-2-oxo-1-azepanyl]butanamide,2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide.

The best results have been obtained with the following compounds:

-   -   (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,    -   (2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,    -   2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,    -   (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,    -   2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

It has now been found that compounds of formula I and theirpharmaceutically acceptable salts are useful in a variety ofpharmaceutical indications.

For example, the compounds according to the invention are useful for thetreatment of epilepsy, epileptogenesis, seizure disorders andconvulsions.

These compounds may also be used for the treatment of other neurologicaldisorders including bipolar disorders, mania, depression, anxiety,migraine, trigeminal and other neuralgia, chronic pain, neuropathicpain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse,stroke, myoclonus, essential tremor, dyskinesia and other movementdisorders, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis,spasticity, Parkinson's disease and other neurodegenerative diseases.

In addition the compounds according to the invention may be used in thetreatment of bronchial asthma, asthmatic status and allergic bronchitis,asthmatic syndrome, bronchial hyperreactivity and bronchospasticsyndromes as well as allergic and vasomotor rhinitis andrhinoconjunctivitis.

Thus, the present invention, in a further aspect, concerns the use of acompound of formula I or a pharmaceutically acceptable salt thereof forthe manufacture of a medicament for the treatment of neurological andother disorders such as mentioned above.

In particular, the present invention concerns the use of a compound offormula I or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of epilepsy, bipolardisorders, chronic pain or neuropathic pain, migraine, bronchial-,asthmatic- or allergic conditions.

In particular, the present invention concerns the use of a compound asdefined above for the manufacture of a medicin for the treatment ofepilepsy, epileptogenesis, seisure disorders and convulsions.

The activity and properties of the active compounds, oral availabilityand stability in vitro or in vivo can vary significantly among theoptical isomers of the disclosed compounds.

In a preferred embodiment, the active compound is administered in anenantiomerically enriched form, i.e., substantially in the form of oneisomer.

The present invention also concerns a method for treating epilepsy,epileptogenesis, seizure disorders, convulsions and other neurologicaldisorders including bipolar disorders, mania, depression, anxiety,migraine, trigeminal and other neuralgia, chronic pain, neuropathicpain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse,stroke, myoclonus, essential tremor, dyskinesia and other movementdisorders, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis,spasticity, Parkinson's disease and other degenerative diseases,bronchial asthma, asthmatic status and allergic bronchitis, asthmaticsyndrome, bronchial hyperreactivity and bronchospastic syndromes as wellas allergic and vasomotor rhinitis and rhinoconjunctivitis, in a mammalin need of such treatment, comprising administering a therapeutic doseof at least one compound as defined above.

The present invention also concerns a method for treating epilepsy,migraine, bipolar disorders, chronic pain or neuropathic pain orbronchial-, asthmatic- or allergic conditions, in a mammal in need ofsuch treatment, comprising adminstering a therapeutic dose of at leastone compound of formula I or a pharmaceutically acceptable salt thereofto a patient.

The present invention also concerns a method for treating epilepsy,epileptogenesis, seizure disorders and convulsions.

The methods of the invention comprise administration to a mammal(preferably human) suffering from above mentioned conditions ordisorders, of a compound according to the invention in an amountsufficient to alleviate or prevent the disorder or condition.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing 5 to 1000 mg,preferably 25 to 500 mg of active ingredient per unit dosage form.

The term “treatment” as used herein includes curative treatment andprophylactic treatment.

By “curative” is meant efficacy in treating a current symptomaticepisode of a disorder or condition.

By “prophylactic” is meant prevention of the occurrence or recurrence ofa disorder or condition.

The term “epilepsy” as used herein refers to a disorder of brainfunction characterised by the periodic and unpredictable occurrence ofseizures. Seizures can be “non-epileptic” when evoked in a normal brainby treatments such as electroshock or chemical convulsants or“epileptic” when evoked without evident provocation.

The term “seizure” as used herein refers to a transient alteration ofbehaviour due to the disordered, synchronous, and rhythmic firing ofpopulations of brain neurones.

The term “migraine” as used herein means a disorder characterised byrecurrent attacks of headache that vary widely in intensity, frequency,and duration. The attacks are commonly unilateral and are usuallyassociated with anorexia, nausea, vomiting, phonophobia, and/orphotophobia. In some cases they are preceded by, or associated with,neurological and mood disturbances. Migraine headache may last from 4hours to about 72 hours. The International Headache Society (IHS, 1988)classifies migraine with aura (classical migraine) and migraine withoutaura (common migraine) as the major types of migraine. Migraine withaura consists of a headache phase preceded by characteristic visual,sensory, speech, or motor symptoms. In the absence of such symptoms, theheadache is called migraine without aura.

The term “bipolar disorders” as used herein refers to those disordersclassified as Mood Disorders according to the Diagnostic and-StatisticalManual of Mental Disorders, 4th edition (Diagnostic and StatisticalManual of Mental Disorders (DSM-IV TM), American Psychiatry Association,Washington, D.C., 1994). Bipolar disorders are generally characterisedby spontaneously triggered repeated (i.e. at least two) episodes inwhich the patient's hyperexcitability, activity and mood aresignificantly disturbed, this disturbance consisting on some occasionsof an elevation of mood and increased energy and activity (mania orhypomania), and in other occasions a lowering of mood and decreasedenergy and activity (depression). Bipolar disorders are separated intofour main categories in the DSM-IV (bipolar I disorder, bipolar Itdisorder, cyclothymia, and bipolar disorders not otherwise specified).

The term “manic episode”, as used herein refers to a distinct periodduring which there is an abnormally and persistently elevated,expansive, or irritable mood with signs of pressured speech andpsychomotor agitation.

The term “hypomania”, as used herein refers to a less extreme manicepisode, with lower grade of severity.

The term “major depressive episode”, as used herein refers to a periodof at least 2 weeks during which there is either depressed mood or theloss of interest or pleasure in nearly all activities with signs ofimpaired concentration and psychomotor retardation.

The term “mixed episode”, as used herein refers to a period of time(lasting at least 1 week) in which the criteria are met both for a manicepisode and for a major depressive episode nearly every day.

The term “chronic pain” as used herein refers to the condition graduallybeing recognised as a disease process distinct from acute pain.Conventionally defined as pain that persists beyond the normal time ofhealing, pain can also be considered chronic at the point when theindividual realises that the pain is going to be a persistent part oftheir lives for the foreseeable future. It is likely that a majority ofchronic pain syndromes involves a neuropathic component, which isusually harder to treat than acute somatic pain.

The term “neuropathic pain” as used herein refers to pain initiated by apathological change in a nerve which signals the presence of a noxiousstimulus when no such recognisable stimulus exists, giving rise to afalse sensation of pain. In other words, it appears that the pain systemhas been turned on and cannot turn itself off.

The activity of the compounds of formula I, or their pharmaceuticallyacceptable salts, as anticonvulsants can be determined in the audiogenicseizures model. The objective of this test is to evaluate theanticonvulsant potential of a compound by means of audiogenic seizuresinduced in sound-susceptible mice, a genetic animal model with reflexseizures. In this model of primary generalised epilepsy, seizures areevoked without electrical or chemical stimulation and the seizure typesare, at least in part, similar in their clinical phenomenology toseizures occurring in man (Löscher W. & Schmidt D., Epilepsy Res.(1998), 2, 145-181; Buchhalter J. R., Epilepsia (1993), 34, S31-S41).Results obtained with compounds of formula I are indicative of a strongpharmacological effect (Table III A, III B).

Another assay indicative of potential anticonvulsant activity is bindingto levetiracetam binding site (LBS) as hereinafter described (Table IIIA, III B).

The activity of the compounds of formula I, or their pharmaceuticallyacceptable salts, in chronic neuropathic pain can be determined inanimal models. For example, chronic neuropathic pain can be modelled bypharmacologically inducing diabetes in rats. In this model, animals showprogressive hyperalgesia to nociceptive stimuli, a symptom generallyobserved in patients with painful peripheral neuropathy (Courteix C,Eschalier, A. and Lavarenne J., Pain (1993), 53, 81-88). This model wasshown to possess a high pharmacological predictivity (Courteix C, BardinM., Chantelauze C., Lavarenne J and Eschalier, A., Pain, 57 (1994)153-160).

The activity of the compounds of formula I, or their pharmaceuticallyacceptable salts, in bipolar disorders can be assessed in animal models.For example, bipolar disorders and especially mania can be modelled bypharmacologically inducing hyperactivity in rats and evaluating theirbehaviour in an Y maze. In such a situation, therapeutic agentseffective in man, like Lithium and sodium valproate decrease thehyperactivity, thus validating the predictivity of the model (Cao B. J.and Peng N. A., Eur. J. Pharmacol. (1993), 237, 177-181; Vale A. L. andRatcliffe F. Psychopharmacology, 91 (1987) 352-355).

Potential anti-asthmatic properties of the compounds of formula I, ortheir pharmaceutically acceptable salts would be tested for in an animalmodel of allergic asthma, in which guinea pigs sensitised to ovalbuminare challenged with the antigen and investigated for changes inpulmonary function and airway inflammatory cell content. (Yamada et al.(1992) Development of an animal model of late asthmatic response inguinea pigs and effects anti-asthmatic drugs. Prostaglandins, 43:507-521).

Activity in any of the above mentioned indications can of course bedetermined by carrying out suitable clinical trials in a manner known toa person skilled in the relevant art for the particular indicationand/or in the design of clinical trials in general.

For treating diseases, compounds of formula I or their pharmaceuticallyacceptable salts may be employed at an effective daily dosage andadministered in the form of a pharmaceutical composition.

Therefore, another embodiment of the present invention concerns apharmaceutical composition comprising an effective amount of a compoundof formula I or a pharmaceutically acceptable salt thereof incombination with a pharmaceutically acceptable diluent or carrier.

To prepare a pharmaceutical composition according to the invention, oneor more of the compounds of formula I or a pharmaceutically acceptablesalt thereof, is intimately admixed with a pharmaceutical diluent orcarrier according to conventional pharmaceutical compounding techniquesknown to the skilled practitioner.

Suitable diluents and carriers may take a wide variety of formsdepending on the desired route of administration, e.g., oral, rectal, orparenteral.

Pharmaceutical compositions comprising compounds according to theinvention can, for example, be administered orally or parenterally,i.e., intravenously, intramuscularly or subcutaneously, intrathecally.

Pharmaceutical compositions suitable for oral administration can besolids or liquids and can, for example, be in the form of tablets,pills, dragees, gelatine capsules, solutions, syrups, and the like.

To this end the active ingredient may be mixed with an inert diluent ora non-toxic pharmaceutically acceptable carrier such as starch orlactose. Optionally, these pharmaceutical compositions can also containa binder such as microcrystalline cellulose, gum tragacanth or gelatine,a disintegrant such as alginic acid, a lubricant such as magnesiumstearate, a glidant such as colloidal silicon dioxide, a sweetener suchas sucrose or saccharin, or colouring agents or a flavouring agent suchas peppermint or methyl salicylate.

The invention also contemplates compositions which can release theactive substance in a controlled manner. Pharmaceutical compositionswhich can be used for parenteral administration are in conventional formsuch as aqueous or oily solutions or suspensions generally contained inampoules, disposable syringes, glass or plastics vials or infusioncontainers.

In addition to the active ingredient, these solutions or suspensions canoptionally also contain a sterile diluent such as water for injection, aphysiological saline solution, oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents, antibacterial agents suchas benzyl alcohol, antioxidants such as ascorbic acid or sodiumbisulphite, chelating agents such as ethylene diamine-tetra-acetic acid,buffers such as acetates, citrates or phosphates and agents foradjusting the osmolarity, such as sodium chloride or dextrose.

These pharmaceutical forms are prepared using methods which areroutinely used by pharmacists.

The amount of active ingredient in the pharmaceutical compositions canfall within a wide range of concentrations and depends on a variety offactors such as the patient's sex, age, weight and medical condition, aswell as on the method of administration. Thus the quantity of compoundof formula I in compositions for oral administration is at least 0.5% byweight and can be up to 80% by weight with respect to the total weightof the composition.

In accordance with the invention it has also been found that thecompounds of formula I or the pharmaceutically acceptable salts thereofcan be administered alone or in combination with other pharmaceuticallyactive ingredients. Non-limiting examples of such additional compoundswhich can be cited for use in combination with the compounds accordingto the invention are antivirals, antispastics (e.g. baclofen),antiemetics, antimanic mood stabilizing agents, analgesics (e.g.aspirin, ibuprofen, paracetamol), narcotic analgesics, topicalanaesthetics, opioid analgesics, lithium salts, antidepressants (e.g.mianserin, fluoxetine, trazodone), tricyclic antidepressants (e.g.imipramine, desipramine), anticonvulsants (e.g. valproic acid,carbamazepine, phenytoin), antipsychotics (e.g. risperidone,haloperidol), neuroleptics, benzodiazepines (e.g. diazepam, clonazepam),phenothiazines (e.g. chlorpromazine), calcium channel blockers,amphetamine, clonidine, lidocaine, mexiletine, capsaicin, caffeine,quetiapine, serotonin antagonists, β-blockers, antiarrhythtmics,triptans, ergot derivatives.

Of particular interest in accordance with the present invention arecombinations of at least one compound of formula I or a pharmaceuticallyacceptable salt thereof and at least one compound inducing neuralinhibition mediated by GABA_(A) receptors. The compounds of formula Iexhibit a potentiating effect on the compounds inducing neuralinhibition mediated by GABA_(A) receptors enabling, in many cases,effective treatment of conditions and disorders under reduced risk ofadverse effects.

Examples of compounds inducing neural inhibition mediated by GABA_(A)receptors include the following: benzodiazepines, barbiturates,steroids, and anticonvulsants such as valproate, vigabatrin, tiagabineor pharmaceutical acceptable salts thereof.

Benzodiazepines include the 1,4 benzodiazepines, such as diazepam andclonazepam, and the 1,5-benzodiazepines, such as clobazam. Preferredcompound is clonazepam.

Barbiturates include phenobarbital and pentobarbital. Preferred compoundis phenobarbital.

Steroids include adrenocorticotropic hormones such as tetracosactideacetate, etc.

Anticonvulsants include hydantoins (phenytoin, ethotoin, etc),oxazolidines (trimethadione, etc.), succinimides (ethosuximide, etc.),phenacemides (phenacemide, acetylpheneturide, etc.), sulfonamides(sulthiame, acetazolamide, etc.), aminobutyric acids (e.g.gamma-amino-beta-hydroxybutyric acid, etc.), sodium valproate andderivatives, carbamazepine and so on.

Preferred compounds include valproic acid, valpromide, valproatepivoxil, sodium valproate, semi-sodium valproate, divalproex,clonazepam, phenobarbital, vigabatrin and tiagabine.

For the preferred oral compositions, the daily dosage is in the range 5to 1000 milligrams (mg) of compounds of formula I.

In compositions for parenteral administration, the quantity of compoundof formula I present is at least 0.5% by weight and can be up to 33% byweight with respect to the total weight of the composition. For thepreferred parenteral compositions, the dosage unit is in the range 5 to1000 mg of compounds of formula I.

The daily dose can fall within a wide range of dosage units of compoundof formula I and is generally in the range 5 to 1000 mg. However, itshould be understood that the specific doses can be adapted toparticular cases depending on the individual requirements, at thephysician's discretion.

The amount of the active ingredients (compound I and compound inducingneural inhibition mediated by the GABA_(A) receptors) in thepharmaceutical composition of the invention will vary depending on themammal to which the compositions are administered, the disease to betreated, other active ingredients present, etc. Generally, the amount ofthe compound inducing neural inhibition mediated by the GABA_(A)receptors and the amount of compound I for a given composition anddosage form can be readily determined employing routine procedures.

According to another aspect, the invention relates to several processesfor preparing a compound having the general formula (I) as describedabove.

The following process description sets forth certain synthesis routes inan illustrative manner. Other alternative and/or analogous methods willbe readily apparent to those skilled in this art. As used herein inconnection with substituent meanings, “=” means “is” and “≠” means “isother than”.

According to one embodiment, compounds having the general formula (I),wherein A¹=O and X═—CONR⁷R⁸ or —COOR⁹, may be made by the cyclisation ofan aminoester of formula (A) wherein Q¹ represents a linear or branchedC1-4-alkyl. Said aminoester of formula (A) wherein n=0 and R³═COOR¹³ orwherein n=1 and R²═COOR¹³, wherein R¹³ linear or branched alkyl groupoptionally optically active, are obtained by reaction of a compound offormula (B) with an unsaturated diester derivative of formula (C) or(D), respectively, according to the following scheme 1.

The first reaction of compound (B) with compound (C) or (D) leading tothe formation of the compound of formula (A) is described in: Street, L.J., Baker, R., Book, T., Kneen, C. O., MacLeod, A. M., Merchant, K. J.,Showell, G. A., Saunders, J., Herbert, R. H., Freedman, S. B., Harley,E. A., J. Med. Chem. (1990), 33, 2690-2697.

When Q¹ represents a methyl or ethyl, the second reaction convertingcompound of formula (A) into (I) is known by the man skilled in the artand is generally carried out between room temperature and 150° C., inthe presence or not of a catalyst such as acetic acid,hydroxybenzotriazole or 2-hydroxypyridine. When Q¹ does not represent amethyl or ethyl, an ester of formula (A) is hydrolysed under acidic orbasic conditions and then cyclised under conventional peptide synthesisconditions, by using coupling agents, for exampledicyclohexylcarbodiimide (Bodanszky, M., Bodanszky. A., in “Me Practiceof Peptide Synthesis”, Springer Verlag, 1984).

According to another embodiment, compounds of the general formula (I),wherein A¹=O and X═—CONR⁷R⁸ and n=0 may conveniently be made by reactionof a compound of formula (E), wherein X¹ represents a halogen atom,preferably an iodine or a chlorine atom, and X² represents —OQ¹ or ahalogen atom, preferably a chlorine atom, with a compound of formula(F). Said compound of formula (E) may be obtained by opening of alactone of formula (G) in the presence of a halogenating agent, forinstance TMSI or SOCl₂/ZnCl₂, followed if necessary by halogenation ofthe obtained halogenoacid (X²═OH). Furthermore, said compound of formula(G) may be prepared by reaction of a compound of formula (J) with anorganolithium compound of formula R⁴Li in the presence of CuI or, whenin formula (G) R²═H, by reduction of a carboxylate of formula (H)wherein Q⁴ is methyl or ethyl, in the presence of a borohydride reagent.All these reactions are depicted schematically in the following scheme2.

The reaction of the compound of formula (J) with the organolithiumcompound of formula R⁴Li in the presence of CuI may be carried outaccording to the procedures described in: Alexakis, A., Berlan, J.,Besace, Y., Tetrahedron Lett. (1986), 27, 1047-1050 and in: Lipshutz, B.H., Ellsworth, E. L., Siahaan, T., J. Am. Chem. Soc. (1989), 111,1351-1358.

Opening of the lactone of formula (G) may be performed according to theprocedure described in: Mazzini, C., Lebreton, J., Alphand, V.,Furstoss, R., Tetrahedron Lett. (1998), 38, 1195-1196 and in Olah, G.A., Narang, S. C., Gupta, B. G. B., Malhotra, R., J. Org. Chem. (1979),44, 1247-1250. Halogenation (X²=halogen) or esterification (X²=OQ¹) ofthe obtained haloalkanoic acid (X²═OH) may be performed under anyconditions known to the person skilled in the art.

The reaction of a compound of formula (E) with a compound of formula (F)forming compound () may be carried out in an inert solvent, for exampledichloromethane, at a temperature of about 0° C. in the presence of aphase transfer catalyst, such as tetrabutylammonium bromide in thepresence of powdered potassium hydroxide (Patent Application GB 2225322A).

According to yet another embodiment, compounds of the general formula(I), wherein A¹=O and X═—COOR⁹, R⁹ representing an alkyl group, may alsobe prepared by reaction of a compound of formula (K) wherein Mrepresents an alkli metal, with a compound of formula (L) wherein X³represents a halogen atom, according to the following scheme 3.

Compounds of formula (K) may be prepared according to the proceduredescribed in: Georg, G., Guan, X., Kant, J., Bioorg. Med. Chem. Lett.(1991), 1, 125.

Alternatively, compounds of formula (K) wherein n=0 may be preparedaccording to the procedure described in: Koelsch, C. F., J. Am. Chem.Soc. (1943), 65, 2093-2095.

According to yet a further embodiment, the invention relates to aprocess for preparing a compound of general formula (I), wherein A¹=Oand X═—CONR⁷R⁸ and none of the groups R¹, R², R³, R⁴, R⁵ and R⁶ beingsubstituted by carboxylic or sulfonic acids or esters or ketone, whereinsaid process comprises the ammonolysis of the corresponding compoundwherein X═—COOR⁹, R⁹ being a hydrogen atom or a linear or branchedC1-4-alkyl group. Alternatively, transformation into the amino form maybe done under conventional peptidic synthesis conditions using couplingagents, for example alkyl chloroformate or dicyclohexylcarbodiimide.

Other processes for preparation of compounds of the general formula (I)and intermediates are known by the man skilled in the art.

For instance, compounds of formula (I) wherein A¹=O, X═CONR⁷R⁸, and oneof the groups R¹, R², R³, R⁴, R⁵ and R⁶ represents -G³-COOCH₃, G³ beinga bond or an alkylene group, are key synthesis intermediates forcorresponding compounds wherein one of the groups R¹, R², R³, R⁴, R⁵ andR⁶ represents -G³-CH₂0H (March, J., “Advanced Organic Chemistry. ThirdEdition”, John Wiley & Sons, (1985), 1101-1102).

Furthermore, compounds of formula (I) wherein A¹=O, X═CONR⁷R⁸, and oneof the groups R¹, R², R³, R⁴, R⁵ and R⁶ represents -G³-CH₂OH, G³ being abond or an alkylene group, are key synthesis intermediates forcorresponding compounds wherein one of the groups R¹, R², R³, R⁴, R⁵ andR⁶ represents -G³-CH₂X³ or -G³-CHO, wherein X³ represents a chlorine, abromine or a iodine atom, or a group of formula —)—SO₂—R¹⁴ wherein R¹⁴represents an alkyl or an aryl group. These transformations may beperformed under any conditions known to the person skilled in the art.

In addition, compounds of formula I wherein A¹=O, X═CONR⁷R⁸, and one ofthe groups R¹, R², R³, R⁴, R⁵ and R⁶ represents -G³-CH₂OSO₂R¹⁴, G³ beinga bond or an alkylene group and R¹⁴ being a methyl or a tolyl group, arekey synthesis intermediates for corresponding compounds wherein one ofthe groups R¹, R², R³, R⁴, R⁵ and R⁶ represents -G³-CH₂N₃ or -G³-CH₂X⁴,wherein X⁴ represents an halogen atom. These transformations may beperformed under any conditions known to the person skilled in the art.

Finally, compounds of formula I wherein A¹=O, X═CONR⁷R⁸, and one of thegroups R¹, R², R³, R⁴, R⁵ and R⁶ represents -G³-CHO, G³ being a bond oran alkylene group, are key synthesis intermediates for correspondingcompounds wherein one of the groups R¹, R², R³, R⁴, R5 and R⁶ represents-G³-R¹⁵ wherein R¹⁵ represents a vinyl group not substituted, mono- ordi-substituted by halogen atoms or alkyl groups (Wittig type reaction).

According to a last embodiment, the present invention encompasses any ofthe intermediates prepared by any of the processes described above.

Representative intermediates of this invention as defined above areselected from the group consisting of methyl1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-(3S)-3-piperidinecarboxylate andmethyl1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-(3R)-3-piperidinecarboxylate andtheir mixtures,(2S)-2-[(5R)-5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide and(2S)-2-[(5S)-5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide and theirmixtures,1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-(3R)-3-piperidinyl}methylmethanesulfonate and(1-[(1S)1-(aminocarbonyl)propyl]-6-oxo-(3S)-3-piperidinyl}methylmethanesulfonate and their mixtures, 5-phenyl-2-piperidinone, ethyl2-(2-oxo-5-phenyl-1-piperidinyl)butanoate, ethyl7-oxo-4-azepanecarboxylate, ethyl1-[1-(tert-butoxycarbonyl)propyl]-7-oxo-4-azepanecarboxylate,2-[5-(ethoxycarbonyl)-2-oxo-1-azepanyl]butanoic acid,1-[1-(aminocarbonyl)propyl]-7-oxo-4-azepanecarboxylate,2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide.

In the preparation processes according to the invention, the reactionproducts may be isolated from the reaction medium and, if necessary,further purified according to methodologies generally known in the artsuch as, for example extraction, crystallization, distillation,trituration and chromatography, or any combination of the same.

When compounds of formula I present one or several stereogenic centres,and that non-steroselective methods of synthesis are used, resolution ofthe mixture of stereoisomers can best be effected in one or severalsteps, involving generally sequential separation of mixtures ofdiastereomers into their constituting racemates, using preferablychromatographic separations on achiral or chiral phase in reversed orpreferably in direct mode, followed by at least one ultimate step ofresolution of each racemate into its enantiomers, using most preferablychromatographic separation on chiral phase in reversed or preferably indirect mode. Alternatively, when partly stereoselective methods ofsynthesis are used, the ultimate step may be a separation ofdiastereomers using preferably chromatographic separations on achiral orchiral phase in reversed or preferably in direct mode.

Some of the intermediates are known compounds or may be preparedaccording to art-known procedures.

The present compounds of this invention differ from the art by theirstructure and by their favourable pharmacological properties. Thefollowing examples are provided for illustrative purposes only and arenot intended, nor should they be construed, as limiting the invention inany manner. Those skilled in the art will appreciate that routinevariations and modifications of the following examples can be madewithout exceeding the spirit or scope of the invention.

EXAMPLES Example 1 Analytical Characterization of 6- and 7-RingCompounds

Unless specified otherwise in the examples, characterization of thecompounds was performed according to the following methods:

NMR spectra are recorded on a BRUKER AC 250 Fourier Tansform NMRSpectrometer fitted with an Aspect 3000 computer and a 5 mm ¹H/¹³C dualprobehead or BRUKER DRX 400 FT NMR fitted with a SG Indigo² computer anda 5 mm inverse geometry ¹H/¹³C/¹⁵N triple probehead. The compound isstudied in DMSO-d₆ (or CDCl₃) solution at a probe temperature of 313 Kand at concentrations ranging from 2 to 20 mg/ml. The instrument islocked on the deuterium signal of DMSO-d₆ (or CDCl₃). Chemical shiftsare given in ppm downfield from TMS taken as internal standard.

Mass spectrometric measurements in LC/MS mode are performed as follows:

HPLC conditions

Analyses are performed using a WATERS Alliance HPLC system mounted withan INERTSIL ODS 3-, DP 5 μm, 250×4.6 mm column.

The gradient runs from 100% solvent A (acetonitrile, water, TFA(10/90/0.1, v/v/v)) to 100% solvent B (acetonitrile, water, TFA(90/10/0.1, v/v/v)) in 7 min with a hold at 100% B of 4 min. The flowrate is set at 2.5 mni/min and a split of 1/10 is used just before APIsource. The chromatography is carried out at 30° C.

MS conditions

Samples are dissolved in acetonitrile/water, 70/30, v/v at theconcentration of about 250 μgr/ml. API spectra (+or −) are performedusing a FINNIGAN (San Jose, Calif., USA) LCQ ion trap mass spectrometer.APCI source operates at 450° C. and the capillary heater at 160° C. ESIsource operates at 3.5 kV and the capillary heater at 210° C.

Mass spectrometric measurements in EI/DIP mode are performed as follows:samples are vaporized by heating the probe from 50° C. to 250° C. in 5min. EI (Electron Impact) spectra are recorded using a FINNIGAN (SanJose, Calif., USA) TSQ 700 tandem quadrupole mass spectrometer. Thesource temperature is set at 150° C.

Specific rotation is recorded on a Perkin-Elmer MC241 or MC341polarimeter. The angle of rotation is recorded at 25° C. on 1% solutionsin MeOH. For some molecules, the solvent is CH₂Cl₂ or DMSO, due tosolubility problems.

Water content is determined using a Metrohm microcoulometric KarlFischer titrator.

Preparative chromatographic separations are performed on silicagel 60Merck, particle size 15-40 μm, reference 1.15111.9025, using in-housemodified Jobin Yvon-type axial compression columns (80 mm i.d.), flowrates between 70 and 150 ml/min. Amount of silicagel and solventmixtures are as described in individual procedures.

Preparative chiral chromatographic separations are performed on a DAICELChiralpak AD 20 μm, 100*500 mm column using an in-house build instrumentwith various mixtures of lower alcohols and C₅ to C₈ linear, branched orcyclic alkanes at ±350 ml/min. Solvent mixtures are as described inindividual procedures.

Melting points are determined on a Büchi 535 Totoli-type fusionometre,and are not corrected, or by the onset temperature on a Perkin Elmer DSC7.

Unless specified otherwise in the examples, the compounds are obtainedin the neutral form.

Example 2 Preparation of Intermediates 2.1. Synthesis of methyl1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-piperidinecarboxylate 1 and 2

In a 100 ml three necked flask fitted with magnetic stirrer and refluxcondenser, under inert atmosphere, 19 g (186 mmoles, 2.66 eq) of(S)-2-aminobutanamide 22 and 12 g (70 mmoles, 1 eq) of dimethyl2-methylenepentanedioate 21 were dissolved in 50 ml of MeOH. 5 ml ofacetic acid were added and the mixture was brought to reflux for 7 days.After cooling down, it was concentrated to dryness, dissolved in CH₂Cl₂,washed successively with water, 0.5 N HCl and brine, dried over MgSO₄and concentrated to dryness to give 17.8 g of crude amide ester as amixture of diastereomers. It was purified by PrepLC (1 kg SiO₂,CH₂Cl₂/MeOH/NH₄OH, 97.25/2.5/0.25) to give 6.8 g of diastereoisomer 1(first eluted) and 4.59 g of diastereoisomer 2 (second eluted), 67%yield. Both were recrystallised from ethyl acetate/hexane.

2.2. Synthesis of(2S)-2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide 3

In a 250 ml three necked flask fitted with magnetic stirrer and refluxcondenser, under inert atmosphere, 6.29 g (26 mmoles, 1 eq) of methyl1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-piperidinecarboxylate 1 weredissolved in 35 ml of EtOH and the mixture cooled down to 0° C. 2.5 g(66 mmoles, 9.5 eq) of solid NaBH₄ were then added by portions over 1.5hour, all the while maintaining the temperature around 0° C. After 2hours, the temperature was raised to 12° C. for 1 hour, and loweredagain to 0° C. 10 ml of a saturated solution of NH₄Cl were added slowly,followed by 10 ml of acetone, and the mixture was left 1 hour at 0° C.The mixture was filtered, the precipitate washed with 3×10 ml of EtOHand the combined organic fractions concentrated to dryness to give 5.9 gof crude alcohol. It was purified by PrepLC (500 g SiO₂, CH₂Cl₂/MeOH,90/10) to give 2.6 g of(2S)-2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide 3, (52% yield).

Compound such as(2S)-2-14-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide can besynthesized in an analogous way.

2.3. Synthesis of1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-piperidinyl}methylmethanesulfonate 23

In a 100 ml three necked flask fitted with magnetic stirrer, droppingfunnel and reflux condenser under inert atmosphere, 1.9 g (8.8 mmoles, 1eq) of (2S)-2-15-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide 3 weresuspended in 50 ml of acetone and cooled down to 0° C. 2.5 ml (17.8mmoles, 2 eq) of dry triethylamine were added in one portion, followedby dropwise addition of a solution of 0.75 ml (8.8 mmoles, 1 eq) ofmethanesulfonyl chloride in 5 ml of acetone, all the while maintainingthe temperature below 4° C. After 3 hours, the mixture was filtered, theresidue washed with acetone and the combined organic phases concentratedto dryness to give 3.4 g of crude1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-piperidinyl)methylmethanesulfonate. It was purified by PrepLC (400 g SiO₂, CH₂Cl₂/MeOH,96/4) to give 1.4 g of pure methanesulfonate 23, (62% yield).

Compound such as1-[(1S)-1-(aminocarbonyl)propyl]-2-oxo-4-piperidinyl}methylmethanesulfonate 24 can be synthesized in an analogous way.

Example 3 Synthesis of(2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide 7

In a 50 ml three necked flask fitted with magnetic stirrer and refluxcondenser, under inert atmosphere, 1.4 g (5.1 mmoles, 1 eq) of1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-piperidinyl}methylmethanesulfonate 23 were dissolved in 15 ml of DMF. 400 mg (6.15 mmoles,1.2 eq) of solid sodium azide were added in one portion, and the mixturewas heated up to 80° C. for 1 hour. The DMF was evaporated in vacuum,the residue suspended in CH₂Cl₂ and the precipitate filtered off. Thefiltrate was concentrated to dryness to give 1 g of crude material. Itwas purified by PrepLC (200 g SiO₂, CH₂Cl₂/MeOH, 97/3) to give 500 mg ofpure azide 7, 45% yield.

Example 4 Synthesis of(2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide 13

In a 150 ml three necked flask fitted with magnetic stirrer and refluxcondenser, under inert atmosphere, 6.88 g (23.5 mmoles) of{1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-piperidinyl}methylmethanesulfonate 24 were dissolved in 86 ml of THF. 3.9 g (25.9 mmoles,1.1 eq) of sodium iodide were added in one portion and the mixture wasbrought to reflux. After 5 hours, 780 mg (5.2 mmoles, 0.22 eq) of sodiumiodide were added and reflux continued for a total of 10 hours. Aftercooling down to 0° C., the mixture was filtered, the precipitate washedwith THF, the combined organic fractions concentrated to dryness andpurified by PrepLC (800 g SiO₂, CH₂Cl₂/MeOH, 95/5) to give 7.21 g ofcrude compound. It was crystallised from 80 ml ethanol to give 5 g ofpure iodide 13, 66% yield.

Example 5 Preparation of ethyl 2-(2-oxo-5-phenyl-1-piperidinyl)butanoate26

Synthesis of the 5-phenyl-2-piperidinone 25: Koelsch, J. Amer. Chem.Soc. (1943), 65, 2093; the racemate was resolved by Chiral PrepLC(Chiralpak AD, petroleum ether/isopropanol, 90/10, 20° C.).

In a 11 three necked flask fitted with reflux condenser, magneticstirrer and dropping funnel under inert atmosphere, 9.8 g (87 mmoles) ofpotassium t-butoxide were suspended in 600 ml of dry toluene. 11.8 g (67mmoles) of 5-phenyl-2-piperidinone 25 were added, and the mixturestirred for 30 min. 17 g (87 mmoles) of ethyl 2-bromobutanoate wereadded and the temperature raised to 70° C. for 5 hours. 600 ml of ethylacetate were added, the solution was washed twice with brine, theorganic phase dried over magnesium sulfate, filtered and concentrated todryness. The residue was purified by PrepLC (1 kg SiO₂, CH₂Cl₂/EtOH,97.5/2.5) to give 3.7 g of pure ester 26 as a mixture of diastereomers,70.4% yield.

Compound such as methyl1-[1-(aminocarbonyl)propyl]-2-oxo-4-piperidinecarboxylate can besynthesized in an analogous way.

Example 6 Preparation of 2-(2-oxo-5-phenyl-1-piperidinyl)butanamide 9,10, 11 and 12

In a 11 three necked flask fitted with reflux condenser, magneticstirrer and a gas inlet tube dipping in the solution, 13.6 g (47 mmoles)of ethyl 2-(2-oxo-5-phenyl-1-piperidinyl)butanoate 26 were dissolved in800 ml of methanol containing 22 mg of dissolved sodium. Gaseous ammoniawas bubbled through the solution, and the saturated solution kept atroom temperature for 3 days, while occasionally resaturating withammonia. After completion of the reaction, the solution was concentratedto dryness. The residue was purified by PrepLC (1 kg SiO₂, CH₂Cl₂/MeOH,95/5) to give 10.1 g of butanamide. The diastereoisomers were thenseparated (Chiralpak AD, ethanol) to give 4.5 g of diastereoisomer 11(first eluted) and 4.3 g of diastereoisomer 12 (second eluted) (72%).Both were recrystailised from ethanol.

Example 7 Method for Preparation of 7-Ring Compounds

7.1. Preparation of ethyl 7-oxo-4-azepanecarboxylate 28

In a 250 ml three necked flask fitted with reflux condenser, magneticstirrer and dropping funnel under inert atmosphere, 5.6 ml (5.98 g, 34mmoles, 1 eq) of ethyl 4-oxocyclohexanecarboxylate 27 were dissolved in50 ml of CHCl₃. 6.65 g (102 mmole, 3 eq) of sodium azide were added,followed by 22.1 ml (32.8 g, 341 mmoles, 10 eq) of methanesulfonic aciddissolved in 20 ml of over 30 min. The mixture was heated to reflux for1 hour and cooled down to 10° C. 200 ml of saturated sodium bicarbonatesolution were added, the mixture decanted and the aqueous phaseextracted with 3×150 ml of CHCl₃, the combined organic phases were driedover magnesium sulfate, filtered and concentrated to dryness. Theresidue was purified by PrepLC (800 g SiO₂, CH₂Cl₂/MeOH, 97/3) to give5.1 g of crude compound. It was crystallised from 40 ml of diethyletherto give 4.41 g of pure ester 28, 70% yield.

7.2. Preparation of ethyl1-[1-(tert-butoxycarbonyl)propyl]-7-oxo-4-azepanecarboxylate 29

In a 150 ml three necked flask fitted with reflux condenser, magneticstirrer and dropping funnel under Inert atmosphere, 5.09 g (27.5 mmoles,1 eq) of ethyl 7-oxo-4-azepanecarboxylate 28 and 12.27 g (55 mmoles, 2eq) of tert-butyl 2-bromobutanoate were dissolved in 70 ml ofacetonitrile. The temperature was raised to 50° C. and 1.32 g (55mmoles, 2 eq) of sodium hydride were added portionwise (exothermicl).The mixture was stirred one more hour at 50° C. and concentrated todryness, the residue was poured on ice/water and neutralised with solidammonium chloride. The mixture was extracted three times with CH₂Cl₂,the combined organic phases were dried over magnesium sulfate, filteredand concentrated to dryness. The residue was purified by PrepLC (1 kgSiO₂, CH₂Cl₂/MTBE, 85/15) to give 8.5 g of pure diester 29, 69% yield.

7.3. Preparation of 2-[5-(ethoxycarbonyl)-2-oxo-1-azepanyl]butanoic acid30

In a 25 ml three necked flask fitted with magnetic stirrer and droppingfunnel under inert atmosphere, 1 g (3.1 mmoles) of pure ethyl1-[1-(tert-butoxycarbonyl)propyl]-7-oxo-4-azepanecarboxylate 29 wasdissolved in 5 ml of CH₂Cl₂. The mixture was cooled down to 0° C., 5 mlof trifluoroacetic acid was added. The mixture was kept at 0° C. understirring for 24 hours, concentrated to dryness and used as such in thenext step.

7.4. Preparation of ethyl1-[1-(aminocarbonyl)propyl]-7-oxo-4-azepanecarboxylate 31

In a 250 ml three necked flask fitted with reflux condenser, magneticstirrer and dropping funnel under inert atmosphere, 5.48 g (20.2 mmoles,1 eq) of 2-t5-(ethoxycarbonyl)-2-oxo-1-azepanyl]butanoic acid 30 weredissolved in 150 ml of ethyl acetate, and 7.44 g (40.4 mmoles, 2 eq) ofpentafluorophenol and 8.34 g (40.4 mmoles, 2 eq) ofdicyclohexycarbodiimide were added, and the mixture kept under stirringat room temperature for 4 hours. 1.86 g of pentafluorophenol and 2.08 gof dicyclohexycarbodiimide (10.7 mmoles, 0.5 eq each) were added, andstirring continued for 1 hour. The mixture was filtered, the residuewashed with ethyl acetate, and the combined organic phases concentratedto dryness. The residue was taken up in 160 ml of CH₂Cl₂, cooled down to0° C. saturated with gaseous ammonia and stirred at that temperature for6 hours with occasional resaturations. The mixture was filtered, theresidue washed with CH₂Cl₂, and the combined organic phases concentratedto dryness. The residue was purified and separated into diastereomers byPrepLC (1 kg SiO₂, CH₂Cl₂/i-PrOH/NH₄OH, 92.5/7/0.5), to give 2.33 g ofthe first eluted diastereoisomer (racemate) and 2.7 g of the seconddiastereomer (racemate), 92% total yield.

Steps 7.5. and 7.6. were described in the previous examples (2.2,2.3 and4).

Compounds with other ring substituents than iodine, or with substituentsat other positions on the ring structure can be synthesized in ananalogous way.

Example 8 Characterization of the Interactions Between a Test Substanceand LBS

LBS stands for Levetiracetam Binding Site, it is an unknown component ofbrain tissue that has been shown to bind levetiracetam (M. Noyer et al.,Eur. J. Pharmacol. (1995), 286, 137-146).

The inhibition constant (K_(i)) of a compound is determined incompetitive binding experiments by measuring the binding of a singleconcentration of a radioactive ligand at equilibrium with variousconcentrations of the unlabeled test substance. The concentration of thetest substance inhibiting 50% of the specific binding of the radioligandis called the IC₅₀. The equilibrium dissociation constant K_(i) isproportional to the IC₅₀ and is calculated using the equation of Chengand Prusoff (Cheng Y. et al., Biochem. Pharmacol. (1972), 22,3099-3108).

The concentration range usually encompasses 6 log units with variablesteps (0.3 to 1 log). Assays are performed in mono- or duplicate, eachK_(i) determination is performed on two different samples of testsubstance. Cerebral cortex from 200-250 g male Sprague-Dawley rats werehomogenised using a Potter S homogeniser (10 strokes at 1,000 rpm;Braun, Germany) in 20 mmol/l Tris-HCl (pH 7.4), 250 mmol/l sucrose(buffer A); all operations were performed at 4° C. The homogenate wascentrifuged at 30,000 g for 15 min. The crude membrane pellet obtainedwas resuspended in 50 mmol/1 Tris-HCl (pH 7.4), (buffer B) and incubated15 min at 37° C., centrifuged at 30,000 g for 15 min and washed twicewith the same buffer. The final pellet was resuspended in buffer A at aprotein concentration ranging from 15 to 25 mg/ml and stored in liquidnitrogen.

Membranes (150-200 μg of protein/assay) are incubated at 4° C. for 120min in 0.5 ml of a 50 mmol/l Tris-HCl buffer (pH 7.4) containing 2mmol/l MgCl₂, 1 to 2.10-9 mol/l of[³H]-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide (levetiracetamanalog, a tritiated radioligand currently used for the labelling ofLBS), and increasing concentrations of the test substance. The nonspecific binding (NSB) is defined as the residual binding observed inthe presence of a concentration of reference substance (e.g. 10⁻³ mol/llevetiracetam) that binds essentially all the receptors. Membrane-boundand free radioligands are separated by rapid filtration through glassfiber filters (equivalent to Whatman GF/C or GF/B; VEL, Belgium)pre-soaked in 0.1% polyethyleneimine and 10⁻³ mol/l levetiracetam toreduce non specific binding. Samples and filters are rinsed by at least6 ml of 50 mmol/l Tris-HCl (pH 7.4) buffer. The entire filtrationprocedure does not exceed 10 seconds per sample. The radioactivitytrapped onto the filters is counted by liquid scintillation in aβ-counter (Tri-Carb 1900 or TopCount 9206, Camberra Packard, Belgium, orany other equivalent counter). Data analysis is perfomed by acomputerized non linear curve fitting method using a set of equationsdescribing several binding models assuming populations of independentnon-interacting receptors which obey to the law of mass. In tables I-Aand I-B the pK_(i) values of various 4- or 5-substituted2-oxo-1-piperidinyl and 5-substituted 2-oxo-1-azepanyl butanamidecompounds are compared to the activity of the non-substitutedlevetiracetam, with a pK_(i) of 6.1±0.1. The lower the K_(i) (the higherthe pK_(i)), the stronger the binding, and thus generally the morepotent the ligand (the drug).

Example 9 Animal Model of Sound-Susceptible Mice

The objective of this test is to evaluate the anticonvulsant potency ofa compound in sound-susceptible mice, a genetic animal model with reflexseizures. In this model of primary generalised epilepsy, seizures areevoked without electrical or chemical stimulation and the seizure typesare, at least in part, similar in their clinical phenomenology toseizures occurring in man (Löscher W. & Schmidt D., Epilepsy Res.(1998), 2, 145-181: Buchhalter J. R , Epilepsia (1993), 34, S31-S41).

Male or female genetically sound-sensitive mice (14-28 g; N=10), derivedfrom a DBA strain originally selected by Dr. Lehmann of the Laboratoryof Acoustic Physiology (Paris) and bred in the UCB Pharma Sectorhusbandry unit since 1978, were used. The experimental design consistedof several groups, one group receiving the vehicle control and the othergroups different doses of the test-compound. The compounds wereadministered intraperitoneally 60 minutes before the induction ofaudiogenic seizures. The range of the doses administered had alogarithmic progression, generally between 1.0×10⁻⁵ mol/kg and 1.0×10⁻³mol/kg, but lower or higher doses were tested if necessary.

For testing, the animals were placed in small cages, one mouse per cage,in a sound-attenuated chamber. After a period of orientation of 30seconds, the acoustic stimulus (90 dB, 10-20 kHz) was delivered for 30seconds via loudspeakers positioned above each cage. During thisinterval, the mice were observed and the presence of the 3 phases of theseizure activity namely wild running, clonic and tonic convulsions, wasrecorded. The proportion of mice protected against wild running, clonicand tonic convulsions, respectively, was calculated.

For active compounds, an ED₅₀ value, i.e. the dose (expressed in molesper kg of test animal) producing 50% protection relative to the controlgroup, together with 95% confidence limits, was calculated using aProbit Analysis (SAS/STAT® Software, version 6.09, PROBIT procedure) ofthe proportions of protected mice for each of the 3 phases of theseizure activity.

In tables I-A and I-B the ED₅₀ value (=AUD CC) for the inhibition ofClonic Convulsions in the Audiogenic seizure test are given. This testis a good animal model for the screening of anticonvulsant and/orantiepileptic compounds. Our reference compound is levetiracetam, with aED₅₀ CC of 180 μmol/kg. The lower the ED₅₀ the more potent the compound.

In the table, the stereochemical information Is contained in the twocolumns headed ‘configuration data’. The second column indicates whethera compound has no stereogenic center (ACHIRAL), is a pure enantiomer(PURE), a racemate (RAC) or is a mixture of two or more stereoisomers,possibly in unequal proportions (MIXT). The first column contains thestereochemical assignment for each recognised center, following theIUPAC numbering used in the preceding column. A number alone indicatesthe existence of both configurations at that center. A number followedby ‘R’ or ‘S’ indicates the known absolute configuration at that center.A number followed by ‘§’ indicates the existence of only one but unknownabsolute configuration at that center. The letter (A, B, C, D) in frontis a way of distinguishing the various enantiomers or racemates of thesame structure.

In the tables, the melting points are in most cases determined by theonset of the DSC curve. When a visual (fusionometer) melting point isgiven, the value is in parenthesis. TABLE I Synthesis intermediates MpLC/MS ¹H IUPAC NAME Configuration (° C.) MH⁺ NMR 1 Methyl1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3- A-1S, 3§ PURE (64-65)piperidinecarboxylate 2 Methyl 1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-B-1S, 3§ PURE  (98-100) piperidinecarboxylate 3(2S)-2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide A-2S, 5§ PURE(138-141) 4 (2S)-2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamideB-2S, 5§ PURE (142-143) 231-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-piperidinyl]methyl A-2S, 5§PURE [1] methanesulfonate 24{1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-piperidinyl}methyl A-2S, 5§PURE [2] methanesulfonate 25 5-phenyl-2-piperidinone A-5§ PURE [3] 26Ethyl 2-(2-oxo-5-phenyl-1-piperidinyl)butanoate A-2, 4§ MIXT [4] 28Ethyl 7-oxo-4-azepanecarboxylate 5 RAC 186 29 Ethyl1-[1-(tert-butoxycarbonyl)propyl]-7-oxo-4- 2, 5 MIXT 328azepanecarboxylate 30 2-[5-(ethoxycarbonyl)-2-oxo-1-azepanyl]butanoicacid 2, 5 MIXT 272 311-[1-(aminocarbonyl)propyl]-7-oxo-4-azepanecarboxylate 2, 5 MIXT 271 322-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide A-2, 5 RAC 229

TABLE II ¹H NMR description ¹H NMR Number ¹H NMR Description Solvent [1]0.79(t, 3H), 1.47-1.68(m, 2H), 1.75-1.93(m, DMSO 2H), 2.12-2.40(m, 3H),3.09(dd, 1H), 3.18(s, 3H), 3.24(dd, 1H), 4.20(d, 2H), 4.84(dd, 1H),6.90(broad s, 1H), 7.15(broad s, 1H) [2] 0.81(t, 3H), 1.49-1.65(m, 2H),1.81-1.91(m, DMSO 2H), 2.09-2.44(m, 3H), 3.11(dd, 1H), 3.18(s, 3H),3.27-3.38(m, 1H), 4.12(d, 2H), 4.82(dd, 1H), 6.92(broad s, 1H),7.1(broad s, 1H) [3] 1.91-2.04(m, 2H), 2.20-2.40(m, 2H), DMSO2.92-3.04(m, 1H), 3.17-3.33(m, 2H), 7.19-7.32(m, 5H), 7.45(broad s, 1H)[4] 0.87 and 0.88(2t, 3H), 1.19 and 1.20(2t, 3H), DMSO 1.69-2.05(m, 4H),2.42-2.49(m, 2H), 3.07-3.13(m, 1H), 3.27-3.35(m, 2H), 4.10(q, 1H),4.75-4.87(2dd, 1H), 7.23-7.35(m, 5H)

TABLE III A 6-ring compounds IUPAC NAME Configuration Mp PKi AUD CC 5(2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide A-2S, 5§ PURE100.6 ++ 1.6E−04 6 (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamideB-2S, 5§ PURE 60.2 +++ 2.0E−04 7(2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide A-2S, 5§ PURE70.1 +++ 1.2E−04 8(2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide B-2§, 5§ PURE96.6 ++ 2.8E−04 9 2-(2-oxo-5-phenyl-1-piperidinyl)butanamide A-2§, 5§PURE 167.0 2.8E−04 10 2-(2-oxo-5-phenyl-1-piperidinyl)butanamide B-2§,5§ PURE 160.7 Inactive 11 2-(2-oxo-5-phenyl-1-piperidinyl)butanamideC-2§, 5§ PURE 158.9 +++ 7.0E−05 122-(2-oxo-5-phenyl-1-piperidinyl)butanamide D-2§, 5§ PURE 167.8 Inactive13 (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide A-2S, 4§ PURE144.0 +++ 1.1E−04 14(2R)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide B-2R, 4§ PURE144.3 Inactive 15 (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamideB-2S, 4§ PURE 153.7 +++ 2.5E−04 16(2R)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide A-2S, 4§ PURE153.3 Inactive

TABLE III B 7-ring compounds LC/MS IUPAC NAME Configuration Mp MH⁺ pKiAUD CC 17 2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide A-2§, 5§ PURE339 + 18 2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide B-2§, 5§ PURE 339+++ 1.3E−04 19 2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide C-2§, 5§PURE 111.7 + Inactive 20 2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamideD-2§, 5§ PURE 111.2 ++ 5.6E−04Legend+ = pKi < 5.5++ = 5.5 ≦ pKi < 6.5+++ = 6.5 ≦ pKi < 7.5++++ = pKi ≧ 7.5inactive = inactive at 1.0E−03

1. Compounds of the formula I, their pharmaceutically acceptable salts,geometrical isomers (including cis and trans, Z and E isomers),enantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers),

wherein A¹ represents an oxygen or a sulfur atom; X is —CONR⁷R⁸, —COOR⁹,—CO—R¹⁰ or CN; R³ and R⁴ are the same or different and each isindependently hydrogen, halogen, nitro, nitrooxy, cyano, carboxy, amido,sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl,heterocycle, acyl derivative, sulfonyl derivative or sulfinylderivative; and; R² and R⁵ are hydrogen; R⁶ is hydrogen, alkyl, aryl or—CH₂-R^(6a) wherein R^(6a) is aryl, heterocycle, halogen, hydroxy,amino, nitro or cyano; R⁷, R⁸ and R⁹ are the same or different and eachis independently hydrogen, hydroxy, alkyl, aryl, heterocycle or an oxyderivative; and R¹⁰ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl,heterocycle or a thio derivative; provided that at least one substituentR chosen from R³ or R⁴ is not hydrogen and that when R⁶ is hydrogen, Xis —CONR⁷R⁸.
 2. The compound according to claim 1 wherein A¹ representsan oxygen atom.
 3. The compound according to claim 1 wherein Xrepresents —CONR⁷R⁸.
 4. The compound according to claim 1 wherein Xrepresents —CONH₂
 5. The compound according to claim 1 wherein R⁶represents hydrogen, a C1-4 alkyl or a CH₂—R^(6a) group wherein R^(6a)represents a heterocycle.
 6. The compound according to claim 1 whereinR⁶ represents a C₁-4-alkyl, preferably ethyl.
 7. The compound accordingto claim 1 wherein the carbon atom to which R⁶ is attached is of the Sconfiguration.
 8. The compound according to claim 1 R³ and R⁴ are thesame or different and each is independently hydrogen; cyano; carboxy;amido; C1-12 alkyl, each optionally substituted by one or moresubstituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy,azido, alkyltio, cycloalkyl, acyl, aryl and heterocycle; C2-12 alkenyl,each optionally substituted by one or more substituents selected fromhalogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;C2-12 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl; acyl derivative of formula —CO—R¹¹, wherein R¹¹ is selectedfrom C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle and aryl;ester of formula —CO—O—R¹¹ wherein R¹¹ is selected from C1-12 alkyl,C2-12 alkenyl, C2-12 alkynyl and aryl; heterocycle selected fromtriazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl,thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl,thiadiazolyl, thiazolyl, thienyl and piperazinyl, each optionallysubstituted by one or more substituents selected from halogen, alkyl,substituted alkyl, alkoxy, nitro, amino, acyl and phenyl; aryl, eachoptionally substitued by one or more substituents selected from C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino, azido,sulfonyl, aryl and nitro.
 9. The compound according to claim 8 whereinR³ and R⁴ are the same or different and each is independently hydrogen;C1-7 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cyclopropyl, acyl and phenyl; C2-6 alkenyl, each optionallysubstituted by one or more substituents selected from halogen, cyano,thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl; C2-6alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl; heterocycle selected from tetrazolyl, pyrrolidinyl,pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each optionallysubstituted by one or more substituents selected from halogen, alkyl,halogen substituted alkyl, acyl, alkoxy, nitro, amino and phenyl;phenyl, each optionally substitued by one or more substituents selectedfrom C1-6 alkyl, C1-6 haloalkyl, halogen, C1-6 alkoxy, amino, azido,sulfonyl, phenyl and nitro.
 10. The compound according to claim 1wherein at least one of the R substituents chosen from the group R³ andR⁴ represents independently C1-4-alkyl or C3-7-cycloalkyl, optionallysubstituted by one or more hydroxy, halogen, lower alkyl or/and azido.11. The compound according to claim 1 wherein at least one of the Rsubstituents chosen from the group R³ and R⁴ represents independentlyvinyl, optionally substituted by one or more halogen or/and lower alkyl.12. The compound according to claim 1 wherein at least one of the Rsubstituents chosen from the group R³ and represents independentlyethynyl, propynyl or butynyl, optionally substituted by one or morehalogen or/and lower alkyl.
 13. The compound according to claim 1wherein at least one of the R substituents chosen from the group R³ andR⁴, represents independently phenyl, optionally substituted by one ormore halogen, lower alkyl, azido and/or nitro.
 14. The compoundaccording to claim 1 wherein at least one of the R substituent chosenfrom the group R³ and R⁴ represents independently 2-or 3-thienyl,optionally substituted by one or more halogen, acyl, cyano and/or loweralkyl.
 15. The compound according to claim 1 wherein R⁴ is hydrogen. 16.The compound according to claim 1 wherein R³ is hydrogen.
 17. Thecompound according to claim 1 selected from the group consisting of2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-propyl-1-piperidinyl)butanamide,2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-phenyl-1-piperidinyl) butanamide,2-12-oxo-5-(2-thienyl)-1-piperidinyl]butanamide,2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide,2-[(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide,2-[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide,2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-4-propyl-1-piperidinyl) butanamide,2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,2-[4-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,2-[2-oxo-4-(2-thienyl)-1-piperidinyl]butanamide,2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide,2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide,2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide.
 18. Thecompound according to claim 1 selected from the group consisting of(2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,(2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-phenyl-1-piperidinyl]butanamide and(2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide.
 19. Thepharmaceutical composition comprising as active ingredient atherapeutically effective amount of a compound according to claim 1 anda pharmaceutically acceptable adjuvant, diluent or carrier.
 20. A methodfor treating epilepsy, epileptogenesis, seizure disorders, convulsionsand other neurological disorders including bipolar disorders, mania,depression, anxiety, migraine, trigeminal and other neuralgia, chronicpain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia,cocaine abuse, stroke, myoclonus, essential tremor, dyskinesia and othermovement disorders, neonatal cerebral haemorrhage, amyotrophic lateralsclerosis, spasticity, Parkinson's disease and other degenerativediseases, bronchial asthma, asthmatic status and allergic bronchitis,asthmatic syndrome, bronchial hyperreactivity and bronchospasticsyndromes as well as allergic and vasomotor rhinitis andrhinoconjunctivitis, in a mammal in need of such treatment, comprisingadministering a therapeutic dose of at least one compound according toclaim
 1. 21. The method according to claim 20 for treating epilepsy,epileptogenesis, seizure disorders and convulsions.
 22. A process forpreparing a compound of general formula (I) of claim 1 wherein A¹represents O and X represents —CONR⁷R⁸ or —COOR⁹, wherein this processcomprises the cyclisation of an aminoester of formula (A) wherein Q¹represents a linear or branched C1-4-alkyl, and wherein said aminoesterof formula (A) wherein n represents O and R³ represents —COOR¹³ whereinR¹³ represents a linear or branched alkyl group optionally opticallyactive, are obtained by reaction of a compound of formula (B) with anunsaturated diester derivative of formula (C) or (D), respectively,according to the following scheme:


23. A process for preparing a compound of general formula (I) of claim 1wherein A¹ represents O and X represents —CONR⁷R⁸ , wherein this processcomprises the reaction of a compound of formula (E), wherein X¹represents a halogen atom, preferably an iodine or a chlorine atom, X²represents —OQ¹ or a halogen atom, wherein Q¹ represents a linear orbranched C1-4-alkyl, with a compound of formula (F); whereby saidcompound of formula (E) is obtained by opening of a lactone of formula(G) in the presence of a halogenating agent, and said compound offormula (G) is prepared by reaction of a compound of formula (J) with anorganolithium compound of formula R⁴Li in the presence of CuI or, whenin formula (G) R²═H, by reduction of a carboxylate of formula (H)wherein Q⁴=methyl or ethyl and in the presence of a borohydride reagent,all reactions according to the following scheme


24. A process for preparing a compound of general formula (I) of claim 1wherein A¹ represents O, n is equal to 0 and X represents —COOR⁹, R⁹representing an alkyl group, wherein this process comprises the reactionof a compound of formula (K) wherein M represents an alkali metal, witha compound of formula (L) wherein X³ represents a halogen atom,according to the following scheme:


25. A process for preparing a compound of general formula (I) of claim 1wherein A¹ represents O, n is equal to 0 and X represents —CONR⁷R⁸, andnone of the substituents R¹, R², R³, R⁴, R⁵ and R⁶ being substituted bycarboxylic or sulfonic acids or esters, or ketone, wherein this processcomprises the ammonolysis of the compound of formula (II), wherein n isequal to 0 and R⁹ represents a hydrogen atom or a linear or branchedC1-4-alkyl group.


26. Intermediates of formula (A) or formula (II) prepared by any of theprocesses according to claims 22 to
 25. 27. Intermediates according toclaim 26 selected from the group consisting of methyl1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-(3S)-3-piperidinecarboxylate andmethyl 1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-(3R)-3-piperidinecarboxylate and theirmixtures, (2S)-2-[(5R)-5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamideand (2S)-2-[(5S)-5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide andtheir mixtures,1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-(3R)-3-piperidinyl}methylmethanesulfonate and{1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-(3S)-3-piperidinyl}methylmethanesulfonate and their mixtures, ethyl2-(2-oxo-5-phenyl-1-piperidinyl)butanoate.